MicroRNAs secreted by human preimplantation embryos and IVF outcome.

OBJECTIVE: To generate an effective embryo prediction model and identify a non-invasive evaluation method by analyzing microRNAs (miRNAs) in embryo culture medium. DESIGN: Analysis of microRNA profiles from spent culture medium of blastocysts with good morphology that did or did not result in pregnancy. SETTING: Clinical and experimental research. PATIENTS: Sixty patients who underwent thawed embryo transfer of blastocysts after intracytoplasmic sperm injection. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The association of miRNA abundance levels secreted by blastocysts in culture medium and implantation success. RESULTS: Our RNA sequencing analysis found a total of 53 differentially expressed miRNAs in the culture media of pregnancy and non-pregnancy groups. Twenty-one miRNAs were analyzed for their potential to predict implantation success. Eight miRNAs (hsa-miR-191-5p, hsa-miR-320a, hsa-miR-92a-3p, hsa-miR-509-3p, hsa-miR-378a-3p, hsa-miR-28-3p, hsa-miR-512-5p, and hsa-miR-181a-5p) were further extracted from the results of a logistic regression analysis of qPCR Ct values. A prediction model for high-quality blastocysts was generated using the eight miRNAs, with an average accuracy of 0.82 by 5-fold cross validation. CONCLUSION: We isolated blastocyst miRNAs that may predict implantation success and created a model to predict viable embryos. Increasing the number of investigated cases and further studying the effect of each miRNA on embryonic development is needed to refine the miRNA-based predictive model.

Measurement of ultra-fast signal progression related to face processing by 7T fMRI.

Given that the brain is a dynamic system, the temporal characteristics of brain function are important. Previous functional magnetic resonance imaging (fMRI) studies have attempted to overcome the limitations of temporal resolution to investigate dynamic states of brain activity. However, finding an fMRI method with sufficient temporal resolution to keep up with the progress of neuronal signals in the brain is challenging. This study aimed to detect between-hemisphere signal progression, occurring on a timescale of tens of milliseconds, in the ventral brain regions involved in face processing. To this end, we devised an inter-stimulus interval (ISI) stimulation scheme and used a 7T MRI system to obtain fMRI signals with a high signal-to-noise ratio. We conducted two experiments: one to measure signal suppression depending on the ISI and another to measure the relationship between the amount of suppression and the ISI. These two experiments enabled us to measure the signal transfer time from a brain region in the ventral visual stream to its counterpart in the opposite hemisphere through the corpus callosum. These findings demonstrate the feasibility of using fMRI to measure ultra-fast signals (tens of milliseconds) and could facilitate the elucidation of further aspects of dynamic brain function.

Estimation of vocational aptitudes using functional brain networks.

The success of human life in modern society is highly dependent on occupation. Therefore, it is very important for people to identify and develop a career plan that best suits their aptitude. Traditional test batteries for vocational aptitudes are not oriented to measure developmental changes in job suitability because repeated measurements can introduce bias as the content of the test batteries is learned. In this study, we attempted to objectively assess vocational aptitudes by measuring functional brain networks and identified functional brain networks that intrinsically represented vocational aptitudes for 19 job divisions in a General Aptitude Test Battery. In addition, we derived classifiers based on these networks to predict the aptitudes of our test participants for each job division. Our results suggest that the measurement of brain function can indeed yield an objective evaluation of vocational aptitudes; this technique will enable a person to follow changes in one's job suitability with additional training or learning, paving a new way to advise people on career development.

Identification of biologically active δ-lactone eicosanoids as paraoxonase substrates.

The mammalian paraoxonases (PONs 1, 2 and 3) are a family of esterases that are highly conserved within and between species. They exhibit antioxidant and anti-inflammatory activities. However, their physiological function(s) and native substrates are uncertain. Previous structure-activity relationship studies demonstrate that PONs have a high specificity for lipophilic lactones, suggesting that such compounds may be representative of native substrates. This report describes the ability of PONs to hydrolyze two bioactive δ-lactones derived from arachidonic acid, 5,6-dihydroxy-eicosatrienoic acid lactone (5,6-DHTL) and cyclo-epoxycyclopentenone (cyclo-EC). Both lactones were very efficiently hydrolyzed by purified PON3. PON1 efficiently hydrolyzed 5,6-DHTL, but with a specific activity about 15-fold lower than PON3. 5,6-DHTL was a poor substrate for PON2. Cyclo-EC was a poor substrate for PON1 and not hydrolyzed by PON2. Studies with the PON inhibitor EDTA and a serine esterase inhibitor indicated that the PONs are the main contributors to hydrolysis of the lactones in human and mouse liver homogenates. Studies with homogenates from PON3 knockout mouse livers indicated that >80% of the 5,6-DHTL and cyclo-EC lactonase activities were attributed to PON3. The findings provide further insight into the structural requirements for PONs substrates and support the hypothesis that PONs, particularly PON1 and PON3, evolved to hydrolyze and regulate a class of lactone lipid mediators derived from polyunsaturated fatty acids.

Benzyl isothiocyanate attenuates the hydrogen peroxide-induced interleukin-13 expression through glutathione S-transferase P induction in T lymphocytic leukemia cells.

We investigated the effect of benzyl isothiocyanate (BITC) on the hydrogen peroxide-induced gene expression of a T-helper-2 cytokine, interleukin (IL)-13, in T lymphocytic leukemia Jurkat cells. The 24-h pretreatment of BITC significantly inhibited the IL-13 expression enhanced by hydrogen peroxide. Although the BITC pretreatment did not change the enhanced level of the phosphorylated c-Jun N-terminal kinase (JNK), it significantly inhibited the nuclear translocation of c-Jun induced by hydrogen peroxide. BITC also increased the protein expression of glutathione S-transferase (GST) isozymes, GSTP1/2, as well as the total GST activity. A GSTP1/2-specific inhibitor, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), significantly counteracted the inhibitory effect of BITC on the hydrogen peroxide-enhanced IL-13 upregulation as well as the c-Jun nuclear translocation. Taken together, these results suggested that BITC inhibits the oxidative stress-mediated IL-13 mRNA expression, possibly through interference of the c-Jun phosphorylation by GSTP.

Attitude and practice of physical activity and social problem-solving ability among university students.

BACKGROUND: Effective social problem-solving abilities can contribute to decreased risk of poor mental health. In addition, physical activity has a favorable effect on mental health. These previous studies suggest that physical activity and social problem-solving ability can interact by helping to sustain mental health. The present study aimed to determine the association between attitude and practice of physical activity and social problem-solving ability among university students. METHODS: Information on physical activity and social problem-solving was collected using a self-administered questionnaire. We analyzed data from 185 students who participated in the questionnaire surveys and psychological tests. Social problem-solving as measured by the Social Problem-Solving Inventory-Revised (SPSI-R) (median score 10.85) was the dependent variable. Multiple logistic regression analysis was employed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for higher SPSI-R according to physical activity categories. RESULTS: The multiple logistic regression analysis indicated that the ORs (95% CI) in reference to participants who said they never considered exercising were 2.08 (0.69-6.93), 1.62 (0.55-5.26), 2.78 (0.86-9.77), and 6.23 (1.81-23.97) for participants who did not exercise but intended to start, tried to exercise but did not, exercised but not regularly, and exercised regularly, respectively. This finding suggested that positive linear association between physical activity and social problem-solving ability (p value for linear trend < 0.01). CONCLUSIONS: The present findings suggest that regular physical activity or intention to start physical activity may be an effective strategy to improve social problem-solving ability.

Factors affecting pregnancy outcomes in young women treated with fertility-preserving therapy for well-differentiated endometrial cancer or atypical endometrial hyperplasia.

BACKGROUND: Patients hoping to preserve their fertility receive conservative treatment with high-dose medroxyprogesterone acetate (MPA) for well-differentiated endometrioid adenocarcinoma (EC) or atypical endometrial hyperplasia (AEH) . Such treatment generally involves frequent intrauterine operations, including dilation and curettage (D&C) and endometrial biopsy (EMB), which could result in endometritis, endometrial thinning, or intrauterine adhesion. In turn, any of these outcomes could adversely affect implantation and pregnancy development. The current study thus aimed to identify factors that might affect pregnancy following conservative treatment by MPA. METHODS: We compared a pregnancy group (45 patients) with a non-pregnancy group (53 patients) of MPA-treated patients to evaluate the factors affecting clinical pregnancy establishment. We undertook a multivariate logistic regression analysis based on factors shown by univariate analysis to be significantly different between the groups. Univariate analysis identified number of D&C, endometrial thickness, duration of MPA administration, age of pregnancy permission (the age at which a patient was first allowed to attempt pregnancy after disappearance of the lesion), period of disappearance of lesions, and recurrence as independent variables. RESULTS: The odds ratios (95 % confidence interval) of multivariate analysis for disease recurrence, endometrial thickness during ovulation, and age of pregnancy permission were 0.283 (0.102-0.785), 1.677 (1.251-2.248), and 0.889 (0.792-0.998), respectively. There was no significant difference in the other independent variables between groups. CONCLUSIONS: We identified three factors considered to affect pregnancy establishment following conservative treatment with MPA: recurrence, endometrial thickness during ovulation, and the age of the pregnancy permission. Introduction of infertility treatment including assisted reproductive technology (ART) soon after achieving tumor disappearance by MPA would therefore be beneficial for patients with disease recurrence, thin endometrium, or a higher age of pregnancy permission.

Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists.

The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in ß-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity.

Neural substrates of Hanja (Logogram) and Hangul (Phonogram) character readings by functional magnetic resonance imaging.

The two basic scripts of the Korean writing system, Hanja (the logography of the traditional Korean character) and Hangul (the more newer Korean alphabet), have been used together since the 14th century. While Hanja character has its own morphemic base, Hangul being purely phonemic without morphemic base. These two, therefore, have substantially different outcomes as a language as well as different neural responses. Based on these linguistic differences between Hanja and Hangul, we have launched two studies; first was to find differences in cortical activation when it is stimulated by Hanja and Hangul reading to support the much discussed dual-route hypothesis of logographic and phonological routes in the brain by fMRI (Experiment 1). The second objective was to evaluate how Hanja and Hangul affect comprehension, therefore, recognition memory, specifically the effects of semantic transparency and morphemic clarity on memory consolidation and then related cortical activations, using functional magnetic resonance imaging (fMRI) (Experiment 2). The first fMRI experiment indicated relatively large areas of the brain are activated by Hanja reading compared to Hangul reading. The second experiment, the recognition memory study, revealed two findings, that is there is only a small difference in recognition memory for semantic transparency, while for the morphemic clarity was much larger between Hanja and Hangul. That is the morphemic clarity has significantly more effect than semantic transparency on recognition memory when studies by fMRI in correlation with behavioral study.

deepPGSegNet: MRI-based pituitary gland segmentation using deep learning.

Introduction: In clinical research on pituitary disorders, pituitary gland (PG) segmentation plays a pivotal role, which impacts the diagnosis and treatment of conditions such as endocrine dysfunctions and visual impairments. Manual segmentation, which is the traditional method, is tedious and susceptible to inter-observer differences. Thus, this study introduces an automated solution, utilizing deep learning, for PG segmentation from magnetic resonance imaging (MRI). Methods: A total of 153 university students were enrolled, and their MRI images were used to build a training dataset and ground truth data through manual segmentation of the PGs. A model was trained employing data augmentation and a three-dimensional U-Net architecture with a five-fold cross-validation. A predefined field of view was applied to highlight the PG region to optimize memory usage. The model's performance was tested on an independent dataset. The model's performance was tested on an independent dataset for evaluating accuracy, precision, recall, and an F1 score. Results and discussion: The model achieved a training accuracy, precision, recall, and an F1 score of 92.7%, 0.87, 0.91, and 0.89, respectively. Moreover, the study explored the relationship between PG morphology and age using the model. The results indicated a significant association between PG volume and midsagittal area with age. These findings suggest that a precise volumetric PG analysis through an automated segmentation can greatly enhance diagnostic accuracy and surveillance of pituitary disorders.

Micronutrient Antioxidants for Men (Menevit®) Improve Sperm Function by Reducing Oxidative Stress, Resulting in Improved Assisted Reproductive Technology Outcomes.

Oxidative stress (OS) affects men's health and impairs spermatogenesis. Micronutrient antioxidants are available for male infertility as complemental support; however, their efficacy remains debatable. This study aimed to investigate whether antioxidants can help to reduce sperm OS and improve semen analysis and quality. We included 171 male partners of couples planning to undergo assisted reproductive technology (ART). Male partners, aged 29-41 years, of couples intending to conceive were self-selected to take daily antioxidants (n = 84) containing folic acid and zinc, or not to take antioxidants (n = 52) for 6 months. We analyzed the alterations in serum oxidant levels, sperm parameters, OS, and deoxyribonucleic acid fragmentation after 3 and 6 months. Additionally, implantation, clinical pregnancy, and miscarriage rates after vitrified-warmed embryo transfer were compared between those taking antioxidants and those not taking them after 6 months. In men with high static oxidation-reduction potential (sORP), we observed a significant improvement in sperm concentration and sORP. The high-quality blastocyst rate tended to increase, and implantation and clinical pregnancy rates also significantly increased after 6 months of intervention. The micronutrient antioxidants could improve sperm function by reducing OS and improving ART outcomes. Therefore, micronutrient antioxidants may be a viable treatment option for male infertility.

Age-associated telomere shortening in mouse oocytes.

BACKGROUND: Oocytes may undergo two types of aging. The first is induced by exposure to an aged ovarian microenvironment before being ovulated, known as 'reproductive or maternal aging', and the second by either a prolonged stay in the oviduct before fertilization or in vitro aging prior to insemination, known as 'postovulatory aging'. However, the molecular mechanisms underlying these aging processes remain to be elucidated. As telomere shortening in cultured somatic cells triggers replicative senescence, telomere shortening in oocytes during reproductive and postovulatory aging may predict developmental competence. This study aimed to ascertain the mechanisms underlying altered telomere biology in mouse oocytes during reproductive and postovulatory aging. METHODS: We studied Tert expression patterns, telomerase activity, cytosolic reactive oxygen species (ROS) production, and telomere length in fresh oocytes from young versus reproductively-aged female mice retrieved from oviducts at 14 h post-human chorionic gonadotropin (hCG), in vivo or in vitro postovulatory-aged mouse oocytes at 23 h post-hCG. Oocytes were collected from super-ovulated C57BL/6 J mice of 6-8 weeks or 42-48 weeks of age. mRNA and protein expressions of the Tert gene were quantified using real-time quantitative reverse transcriptase polymerase chain reaction (Q-PCR) and immunochemistry. Telomerase activity was measured by a telomeric repeat amplification protocol assay, while telomere length was measured by Q-PCR and quantitative fluorescence in situ hybridization analyses. RESULTS: The abundance of Tert expression in oocytes significantly decreased during reproductive and postovulatory aging. Immunofluorescent staining clearly demonstrated an altered pattern and intensity of TERT protein expression in oocytes during reproductive aging. Furthermore, relative telomerase activity (RTA) in oocytes from reproductively-aged females was significantly lower than that in oocytes from young females. In contrast, RTA in postovulatory-aged oocytes was similar to that in fresh oocytes. Oocytes from reproductively-aged females and postovulatory-aged oocytes showed higher ROS levels than oocytes from young females. Relative telomere length (RTL) was remarkably shorter in oocytes from reproductively-aged females compared to oocytes from young females. However, postovulatory aging had no significant effect on RTL of oocytes. CONCLUSIONS: Long-term adverse effects of low telomerase activity and increased ROS exposure are likely associated with telomere shortening in oocytes from reproductively-aged female mice.

In-vivo human brain molecular imaging with a brain-dedicated PET/MRI system.

Advances in the new-generation of ultra-high-resolution, brain-dedicated positron emission tomography-magnetic resonance imaging (PET/MRI) systems have begun to provide many interesting insights into the molecular dynamics of the brain. First, the finely delineated structural information from ultra-high-field MRI can help us to identify accurate landmark structures, thereby making it easier to locate PET activation sites that are anatomically well-correlated with metabolic or ligand-specific organs in the neural structures in the brain. This synergistic potential of PET/MRI imaging is discussed in terms of neuroscience and neurological research from both translational and basic research perspectives. Experimental results from the hippocampus, thalamus, and brainstem obtained with (18)F-fluorodeoxyglucose and (11)C-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile are used to demonstrate the potential of this new brain PET/MRI system.

Impact of Homocysteine as a Preconceptional Screening Factor for In Vitro Fertilization and Prevention of Miscarriage with Folic Acid Supplementation Following Frozen-Thawed Embryo Transfer: A Hospital-Based Retrospective Cohort Study.

Homocysteine is an amino acid naturally produced in the body and metabolized via the methionine cycle. High homocysteine levels can increase the risk of infertility and pregnancy complications, such as preeclampsia, preterm delivery, miscarriage, and low birth weight. Preconceptional homocysteine levels may be reduced by taking folic acid supplements to reduce the risk of such complications. This cross-sectional, hospital-based study was conducted to examine the role of homocysteine in 1060 infertile women with a history of IVF/intracytoplasmic sperm injection (ICSI) failure. We analyzed whether folic acid intervention altered homocysteine levels and influenced reproductive outcome. We found that a higher homocysteine level was statistically associated with a lower fertilization rate in patients with a history of IVF/ICSI failure. There was an inverse relationship between homocysteine levels and serum 25(OH)VD, and a trend towards lower anti mullerian hormone in the group with higher homocysteine levels. This is the first interventional study to identify that folic acid supplementation improved pregnancy outcomes following freeze embryo transfer (FET) in women with a history of FET failure by monitoring the reduction in homocysteine levels. Therefore, folic acid supplementation and homocysteine level monitoring may constitute a novel intervention for improving IVF/ICSI pregnancy outcomes.

Finding the BOLD effect in brain images.

A brief description of events that led to the finding of BOLD effect in brain images is presented. This is a recollection of what were in this author's mind in pre-1992 period.

Hand shape selection in pantomimed grasping: interaction between the dorsal and the ventral visual streams and convergence on the ventral premotor area.

In visually guided grasping, possible hand shapes are computed from the geometrical features of the object, while prior knowledge about the object and the goal of the action influence both the computation and the selection of the hand shape. We investigated the system dynamics of the human brain for the pantomiming of grasping with two aspects accentuated. One is object recognition, with the use of objects for daily use. The subjects mimed grasping movements appropriate for an object presented in a photograph either by precision or power grip. The other is the selection of grip hand shape. We manipulated the selection demands for the grip hand shape by having the subjects use the same or different grip type in the second presentation of the identical object. Effective connectivity analysis revealed that the increased selection demands enhance the interaction between the anterior intraparietal sulcus (AIP) and posterior inferior temporal gyrus (pITG), and drive the converging causal influences from the AIP, pITG, and dorsolateral prefrontal cortex to the ventral premotor area (PMv). These results suggest that the dorsal and ventral visual areas interact in the pantomiming of grasping, while the PMv integrates the neural information of different regions to select the hand posture. The present study proposes system dynamics in visually guided movement toward meaningful objects, but further research is needed to examine if the same dynamics is found also in real grasping.

Synthesis and evaluation of novel modified γ-lactam prostanoids as EP4 subtype-selective agonists.

To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented.

Effects of Physiological Signal Removal on Resting-State Functional MRI Metrics.

Resting-state fMRIs (rs-fMRIs) have been widely used for investigation of diverse brain functions, including brain cognition. The rs-fMRI has easily elucidated rs-fMRI metrics, such as the fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity (VMHC), and degree centrality (DC). To increase the applicability of these metrics, higher reliability is required by reducing confounders that are not related to the functional connectivity signal. Many previous studies already demonstrated the effects of physiological artifact removal from rs-fMRI data, but few have evaluated the effect on rs-fMRI metrics. In this study, we examined the effect of physiological noise correction on the most common rs-fMRI metrics. We calculated the intraclass correlation coefficient of repeated measurements on parcellated brain areas by applying physiological noise correction based on the RETROICOR method. Then, we evaluated the correction effect for five rs-fMRI metrics for the whole brain: FC, fALFF, ReHo, VMHC, and DC. The correction effect depended not only on the brain region, but also on the metric. Among the five metrics, the reliability in terms of the mean value of all ROIs was significantly improved for FC, but it deteriorated for fALFF, with no significant differences for ReHo, VMHC, and DC. Therefore, the decision on whether to perform the physiological correction should be based on the type of metric used.

Involvement of the intrinsic functional network of the red nucleus in complex behavioral processing.

Previous studies suggested the possibility that the red nucleus (RN) is involved in other cognitive functions than motion per se, even though such functions have yet to be clarified. We investigated the activation of RN during several tasks and its intrinsic functional network associated with social cognition and musical practice. The tasks included finger tapping, n-back, and memory recall tasks. Region of interest for RN was identified through those tasks, anatomical information of RN, and a brain atlas. The intrinsic functional network was identified for RN by an analysis of connectivity between RN and other regions typically involved in seven known resting state functional networks with RN used as the seed region. Association of the RN network with a psychological trait of the interpersonal reactivity index and musical training years revealed subnetworks that included empathy related regions or music practice related regions. These social or highly coordinated motor activity represent the most complex functions ever known to involve the RN, adding further evidence for the multifunctional roles of RN. These discoveries may lead to a new direction of investigations to clarify probable novel roles for RN in high-level human behavior.

DeepParcellation: A novel deep learning method for robust brain magnetic resonance imaging parcellation in older East Asians.

Accurate parcellation of cortical regions is crucial for distinguishing morphometric changes in aged brains, particularly in degenerative brain diseases. Normal aging and neurodegeneration precipitate brain structural changes, leading to distinct tissue contrast and shape in people aged >60 years. Manual parcellation by trained radiologists can yield a highly accurate outline of the brain; however, analyzing large datasets is laborious and expensive. Alternatively, newly-developed computational models can quickly and accurately conduct brain parcellation, although thus far only for the brains of Caucasian individuals. To develop a computational model for the brain parcellation of older East Asians, we trained magnetic resonance images of dimensions 256 × 256 × 256 on 5,035 brains of older East Asians (Gwangju Alzheimer's and Related Dementia) and 2,535 brains of Caucasians. The novel N-way strategy combining three memory reduction techniques inception blocks, dilated convolutions, and attention gates was adopted for our model to overcome the intrinsic memory requirement problem. Our method proved to be compatible with the commonly used parcellation model for Caucasians and showed higher similarity and robust reliability in older aged and East Asian groups. In addition, several brain regions showing the superiority of the parcellation suggest that DeepParcellation has a great potential for applications in neurodegenerative diseases such as Alzheimer's disease.